Current Opinion in Hematology最新文献

Purpose of review: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematological malignancies characterized by complex genetic alterations, leading to poor clinical outcomes. Despite advances in treatment, there is an urgent need for novel therapeutic approaches. This review outlines recent progress in humanized models of MDS and AML and highlight their role in advancing our understanding of these diseases.

Recent findings: Patient derived xenografts (PDXs) were among the first humanized models for studying MDS and AML, allowing researchers to analyze patient-specific cancer properties in vivo . However, they face challenges related to sample availability and consistent engraftment in mice. New methods, including specialized mouse strains and human tissue scaffolds, have been developed to address these issues. Induced pluripotent stem cells (iPSCs) offer the advantage of indefinite expansion and genetic modification, making them valuable for in vitro research, though protocols to enhance their engraftment in vivo are still being refined. Genetically engineered human primary hematopoietic stem and progenitor cells (HSPCs) provide reliable in vivo models with good engraftment in mice, and recent advancements in culture systems and gene-editing techniques are helping to overcome challenges related to ex vivo expansion and genetic modification.

Summary: PDXs, iPSCs, and genetically engineered HSPCs are crucial models for the study of MDS and AML. This review discusses strengths, limitations, and recent advancements of these humanized models, which provide insights into human-specific disease biology and therapeutic development.

Purpose of review: To date, there is relatively limited research investigating changes in red blood cells (RBCs), particularly qualitative changes, in cancer patients and cancer patients receiving treatment. These changes may be important in better understanding cancer-associated anemia, which is the most prevalent hematological disorder in cancer patients with wide-ranging implications on patient care and quality of life. This review aims to summarize available evidence regarding qualitative and quantitative changes in RBCs in individuals with cancer prior to treatment and in patients undergoing treatment.

Recent findings: The most commonly reported changes in RBCs in cancer patients were increased mean corpuscular volume (MCV) and decreased hemoglobin, RBC count, and hematocrit. There were increased lipid peroxidation products and decreased antioxidants. There were increased polyunsaturated fatty acids (PUFAs) and decreased monounsaturated fatty acids (MUFAs) and saturated fatty acids (FAs). Additionally, RBC shape alterations with various atypical morphologies, membrane structure abnormalities, and impaired fluidity were also reported. These and various other reported findings are discussed in depth.

Summary: There are several reported quantitative and qualitative RBC changes in individuals with cancer, with some studies exhibiting conflicting results. Further research is needed to solidify the data and to better understand hematological-associated comorbidities in those patients.

Purpose of review: The aim of this review is to highlight the importance of lipids' intricate and interwoven role in mediating diverse acute myeloid leukemia (AML) processes, as well as potentially novel lipid targeting strategies. This review will focus on new studies of lipid metabolism in human leukemia, particularly highlighting work in leukemic stem cells (LSCs), where lipids were assessed directly as a metabolite.

Recent findings: Lipid metabolism is essential to support LSC function and AML survival through diverse mechanisms including supporting energy production, membrane composition, signaling pathways, and ferroptosis. Recent work has highlighted the role of lipid rewiring in metabolic plasticity which can underlie therapy response, the impact of cellular and genetic heterogeneity in AML on lipid metabolism, and the discovery of noncanonical roles of lipid related proteins in AML.

Summary: Recent findings around lipid metabolism clearly demonstrates their importance to our understanding and therapeutic targeting of AML. We have only begun to unravel the regulation and utilization of lipids in this disease. Further, understanding the layered dynamics of lipid homeostasis could provide novel opportunities to target lipid metabolism in AML and LSCs with the potential of improving outcomes for patients with AML.

Purpose of review: The purpose of this review is to outline current graft versus host disease (GvHD) prophylaxis, in the era of posttransplant cyclophosphamide (PTCY), in patients with malignant and nonmalignant hematologic disorders. The original combination of PTCY with a calcineurin inhibitor (CNI) and mycophenolate (MMF), reported from the Johns Hopkins University in Baltimore, was designed for patients receiving a graft from a donor mismatched at one haplotype, so called haploidentical donor (HAPLO). In the past decade, PTCY has been widely used in HAPLO transplants worldwide, confirming the amazing efficacy of PTCY in preventing GvHD in mismatched grafts.

Recent findings: More recently, PTCY is being tested also in grafts from human leukocyte antigen (HLA) identical related or unrelated donors. In the present review we will also answer several open questions, such as: PTCY and cardiac toxicity; PTCY dose; PTCY timing; PTCY and antithymocyte globulin (ATG); engraftment kinetics; infections; PTCY and leukemia relapse; PTCY and HLA identical grafts.

Summary: PTCY is currently one of the most effective measures to prevent GvHD, and can be customized in different transplant platforms, together with other immunosuppressive agents. There is place for improvement, and several possible modifications of PTCY dose and schedule can be tested in prospective trials.

Purpose of review: DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease.

Recent findings: Large cohort studies have revealed that germline DDX41 variants are heterozygous and predominantly loss-of-function. Acquired mutation of the contralateral DDX41 allele, typically R525H, is present in more than half of patients at disease onset, which occurs after age 50. DDX41 is essential for hematopoiesis and has versatile functions in RNA metabolism and innate immune sensing. Experimental models have suggested that innate immune activation downstream of defects in R-loop resolution and ribosome biogenesis plays a key role in the pathogenesis.

Summary: While intensive investigations unveiled a strong genotype-phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

Purpose of review: Thalassemia and sickle cell disease are among the most frequent monogenic hereditary diseases. Access to transfusions, iron chelation therapies and drugs such as hydroxyurea have improved life expectancy and quality of life. However, these diseases still cause significant disability. The first available curative therapy, bone marrow transplantation, is unfortunately not feasible for all patients. Over the past decade, numerous studies have focused on finding new curative therapies, and many clinical trials have evaluated different gene therapy approaches.

Recent findings: The therapeutic targets focus on adding functional copies of the gene encoding β-globin in defective CD34+ cells, mainly using lentiviral vectors directed towards HSCs. More recently, the focus has shifted to inducing fetal hemoglobin production at therapeutic levels or repairing the underlying molecular defect, using novel gene editing techniques involving CRISPR-Cas9, transcription activation-like effector protein nucleases, zinc finger nucleases and base editing. Preclinical and clinical studies now focus on optimizing how gene therapy is performed and delivered to reduce or eliminate myeloablative treatment and its potential adverse events.

Summary: In this review, we explore the potential to induce fetal hemoglobin production at therapeutic levels or to repair the underlying molecular defect that causes the disease genetically. Here, we review recent gene editing studies that are opening a new era in curative treatment for hemoglobinopathies.

Purpose of review: The lack of optimal treatments for haematological disorders has led to the need for prediction models for diagnosis, therapeutic decision-making and life planning. In this review, the worrying current state of predictive models in the field is discussed.

Recent findings: Here, we reviewed 100 studies on prediction models in this field. Our analysis revealed a concerning state of affairs, with a prevalence of suboptimal research methodologies and questionable statistical practices. This includes insufficient sample sizes, inadequate model evaluations, lack of necessary reports of model results, etc. In this regard, we present statistical considerations in the development and validation process of numerous models. This will provide the reader with the statistical knowledge related to prediction model necessary to assess bias in studies, compare other published models and determine the clinical utility of models.

Summary: Awareness among authors, reviewers and editors of the required statistical considerations is crucial. Reinforcing these in all studies involving prediction models is needed. We all should encourage their use in evaluating existing studies and taking them fully into account in future studies.

Purpose of review: To explore the use of large datasets in predicting and managing cancer-associated venous thromboembolism (CAT) by stratifying patients into risk groups. This includes evaluating current predictive models and identifying potential improvements to enhance clinical decision-making.

Recent findings: Cancer patients are at an elevated risk of developing venous thromboembolism (VTE), which significantly impacts mortality and quality of life. Traditional approaches to risk assessment fail to account for the procoagulant changes associated with cancer, making individualized risk prediction a challenge. Current clinical guidelines as per ASCO recommend risk assessment before chemotherapy and endorse thromboprophylaxis as a standard preventive measure. Since any cancer population is highly heterogeneous in terms of VTE risk, predicting the risk of CAT is an oncological challenge. To address this, different predictive models have been developed to stratify patients by risk, enabling targeted thromboprophylaxis. However, these models vary in accuracy and utility. The present review discusses the pros and cons of these different models.

Summary: The review examines existing CAT risk prediction models, highlighting their strengths, limitations, and diagnostic performance. It also identifies additional variables that could enhance these models to improve their effectiveness in guiding clinicians toward better risk stratification and treatment decisions for cancer patients.

Purpose of review: Patients with cancer have an increased risk of venous thromboembolism (VTE). Guidelines suggest to use risk assessment tools to guide decisions about thromboprophylaxis, but current tools have modest discriminatory ability. Genetic information from the germline or tumor has the potential to improve VTE prediction. Here, we provide a clinical overview of the current role of genetics in cancer-associated VTE.

Recent findings: Germline mutations, such as factor V Leiden and prothrombin G20210A, are associated with a 2- to 2.5-fold increased VTE risk in patients with cancer. Tumor-specific somatic mutations also contribute to VTE risk, such as ALK rearrangements increasing the risk in nonsmall cell lung cancer and IDH1 mutations decreasing the risk in gliomas. Other somatic mutations associated with VTE independent of tumor type include KRAS , STK11 , MET , KEAP1 , CTNNB1 , and CDKN2B . Incorporating data on germline or somatic mutations in risk scores improves discriminatory ability compared with the Khorana score.

Summary: Specific germline and somatic mutations are associated with an increased VTE risk in patients with cancer and potentially improve performance of clinical risk scores. The increasing and widespread use of genetic testing in cancer care provides an opportunity for further development of prediction models incorporating genetic predictors.